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June 2020

Post Covid-19 Syndrome: Why Covid-19 May Linger

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Getting through Covid-19 seems to be easy for some of us. Although the long-term effects aren’t known yet, few people seem worried about long-lasting damage, especially if they never had severe symptoms.  Maybe people should be concerned: a hill of evidence is starting to accumulate, pointing to long-lasting damage from Covid-19. While it is not surprising that Covid-19 could infect any tissue throughout the body, given the ubiquitous distribution of ACE-II receptors, the real surprise might lie in how and why it pops out again

A likely place to find long-term damage is the brain, since there are many ACE-II receptors in critical areas such as the hypothalamus. Troubling reports of confusion, delirium, memory loss, fatigue, and depression, are some of the long-lasting effects patients are reporting. The viral fatigue can be the only symptom some people ever experience, and for others, it has proven to last for months after their other symptoms went away. For others, biochemical changes leading to chronic depression and anxiety might linger for weeks or months, potentially much longer. The delirium and confusion associated with the brain damage caused by Covid-19 can remain: in the words of one patient, “Covid has killed me” – a reference to the fact that she suffers debilitating confusion, can no longer walk, and suffers from soul-crushing depression.[1]

Perhaps one of the most interesting ways that Covid-19 intersects the brain and at the same time underscores the complex interconnection of the body’s systems concerns how it affects our breathing. In what has called “happy hypoxia” – or more accurately, silent hypoxia – nearly asymptomatic patients have had stunning, profound levels of oxygen deficit. While SPO2 levels below 80% can result in impaired cognition for most people, and below 75% typically results in loss of consciousness, some Covid-19 patients present with far lower levels – as low as 50% – yet seem fine.[2] Fine as in, they’re happily texting away, oblivious to any danger they might be in, and reporting no discomfort related to their breathing. It’s thought that this constellation of symptoms might be due to a lack of communication from the brain centers responsible for breathing. Although more research is needed to support the hypothesis, it could explain the profound hypoxia – and the utter lack of awareness that suffers have.

Other problems also occur and never go away – or they do so in such an asymmetrical fashion that sufferers can be held hostage by symptoms, even when they remit for the occasional good day. A special kind of post-traumatic stress disorder, post-intensive care syndrome, seems to haunt a great many survivors. Some of the condition is psychological: being treated in isolation and breathing with a mechanical ventilator can be extremely traumatic. But other components may be physical: sufferers complain of chest tightness and shortness of breath. Since many will have alveolar damage, and perhaps permanent scarring in their lungs, the seemingly reasonable question of whether these symptoms are primarily psychological becomes a chicken-or-the-egg type of ordeal. Furthermore, post-intensive care syndrome presents commonly as a hospital-acquired delirium. As one critical care fellow at UCSD reported, “I had one patient who came to our ICU recovery clinic, who told me that he was in a half-conscious state the whole time. He thought the nurses were hooking up poisonous snakes to his arms.” [3] About half of long-term (20 days or more) ICU patients seem to have some long-term affliction following their time in the hospital.

Regardless of the differences in manifestation, early March Covid-19 survivors are still showing the symptoms, in some cases, over 100 days later.[4] For many people, the most enduring symptom is intense bouts of viral fatigue. The fatigue often (but not necessarily) presents as irregularly occurring, sudden attacks of body-draining bone-weariness that make it impossible to do anything, sometimes even making it difficult to leave the house. Some sufferers report that it intensifies throughout the day, with milder morning symptoms that give way to debilitating fatigue, usually the afternoon or the evening. Sleeping provides only a brief respite, followed by day after day repetition of the cycle.

Nobody knows how long these things will go on, nor do we know who will get better and who will not. It bears repeating that most cases don’t result in serious disease, and many of us may never even know that we had it. In other words, Covid-19 is not worth panicking over. But it is worth taking seriously.

[1] Cormier, Z. June 22, 2020. Future. How Covid-19 Can Damage the Brain. https://www.bbc.com/future/article/20200622-the-long-term-effects-of-covid-19-infection.

[2]  https://www.nytimes.com/2020/04/20/opinion/sunday/coronavirus-testing-pneumonia.html.

[3] Edwards, E. March 28, 2020Post intensive-care syndrome’: Why some COVID-19 patients may face problems even after recovery < https://www.nbcnews.com/health/health-news/post-intensive-care-syndrome-why-some-covid-19-patients-may-n1166611>.

[4] From testimony on Good Morning Britain. June 24, 2020. <https://www.youtube.com/watch?v=nMbQlzqZZKs>.

Manufacturing Problems in China, Again

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This time it’s the lies that bind.In recent news, which has garnered some attention from the media but not nearly enough, hundreds of Chinese suppliers of medical equipment to U.S. have been discovered using false, faulty, or utterly implausible registration with the FDA. That would not be good any day of the week, but it gets comically worse. Some thirteen hundred plus companies were found using the same address to pawn their wares off on the U.S. FDA. The house is a three-bedroom brick shelter in Wilmington, Delaware, and neither the occupants nor landlord knew anything about any Chinese companies when they were interviewed. The edifice was little more than a ruse for these companies to import their goods into the U.S. using an agency known as CCTC, while the FDA has deemed it has “probable cause to believe CCTC is a fictitious corporation.”

Previous to the medical equipment debacle, federal health officials revoked U.S. authorization for masks made by over 60 Chinese manufacturers that failed to meet standards for the safety of health care workers.  Due to shortages caused by the influx of patients with Covid-19, the U.S. accepted donations of masks, gloves and protective equipment from China.  The Food and Drug Administration allowed the imports based on testing data from the companies, but new U.S. testing revealed the masks to fall far short of the reported test results.  The Chinese were modified N95 masks, which filter at least 95% of particles.  U.S. testing showed dozens of the Chinese masks failed to meet that 95% level, with some masks filtering as little as 20% of particles, according to the CDC.  More than masks and protective equipment are at stake, China is the world’s leading manufacturer for a multitude of products worldwide, from shoes and buttons to Christmas lights.

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A seemingly unrelated anecdote further illustrates a lack of manufacturing oversight in China hails from the food industry. Luckin Coffee, which has been touted among the world’s fastest-growing coffee companies as the Chinese answer to Starbucks, has been the subject of a $311 million dollar accounting scandal. That number represents the dollar value of transactions that were forged by executives to inflate sales figures, and therefore stock prices. Boosting investor confidence under pretenses led to stock market devastation when the bubble burst; however: Luckin stocks fell from over $50 per share in January to $4.39 per share in maid April amidst the growing scandal.

The fabricated figures from Luckin and FDA shenanigans with the CCTC both serve to underscore the sad state of oversight in China. A backlash against the falsification of data is informing calls for stricter regulatory oversight of securities when companies go public, and for a more rigorous auditing process to ensure that published data from Chinese companies are truthful. Domestic Chinese investors, no less than their international counterparts, want to have confidence that their holdings can weather audits without withering at the slightest inquiry. 

In the U.S. it is becoming apparent that the FDA needs to up its game to ensure that it is doing an adequate job of protecting its constituents. While it is true that the companies that exploited regulatory weaknesses in the American marketplace need to be held accountable for their actions, our laxity paved the way for them to find those weaknesses. The FDA’s relaxed enforcement in the wake of Covid-19 is one factor that has negatively affected the quality of goods in the American marketplace, but certainly not the only one. How many people know where their drugs are manufactured? In an age where the ins and outs of API manufacture are proprietary and concealed with trade secrets, how can we know where the medicines on our shelves come from – and more importantly, how do we ensure that our supplies are safe? 

There are two different kinds of safety involved here: freedom from defects and impurities (i.e., product quality) and reliability of sourcing (i.e., supply chain robustness). These issues raise questions about both. The cGMP paradigm is not about quality “tested into” a product, which might miss things. The paradigm is about quality built into a product, which according to the FDA website, “…includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories.” 

This is not idealistic, it is possible, and it’s absolutely imperative that we do this if we want to have confidence in our life-saving medicines.   But are we doing it? 

Mitochondrial Uncoupling: If You Want to Live Longer, Look to the Skies

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Over the years an enormous amount of both scientific and pseudo-scientific speculation has been aimed at explaining prevailing trends in the lifespan of animals,and how we might apply those lessons to humans.

Since clear, observable trends exist with respect to various groups of animals and lifespan, if we can understand the underlying processes behind those trends, we might be able to extend and maximize our own lifespans.  The most obvious trend is body size versus lifespan, which is robust and repeatable, yet has some outliers that offer tantalizing grounds for speculation.

Figure 1 shows the trend between size and lifespan.  The trend lines, both of which have significant scatter, clearly show two trends, with the data broken down to illustrate the difference between flying and non-flying species.  The striking difference between species who can and cannot fly will be immediately available to anyone who has ever kept a parrot – some species can reliably outlive their human owners.

sizeA number of theories exist to explain the differences between these groupings – and why bats and birds live so much longer.  The authors of the study behind Figure 1 [1] point to the differences in predation vulnerability and argue that flying reduces predation and vulnerability to food shortages.  In that respect, flight offers some of the same advantages as large body size, resulting in the anomalously longer lifespans enjoyed by bats and birds.  The only problem with this hypothesis is that a Malthusian distribution should ensue, and when these populations explode to the very limits of their ecological carrying capacity, one would expect that these advantages would be nullified.  Yet the differences persist.

An alternative view is that animals adapted for flight have a chemical advantage related to flying.  Their tissues express larger quantities of mitochondrial uncoupling proteins, which allow the “leak” of H+ without producing ATP in the mitochondria.  This means that they can “throw away” excess energy produced when they are at rest, necessary because their cellular machinery is designed to process huge amounts of energy during periods of flight.  Tossing the protons made by oxidative respiration has the side benefit that reactive oxygen species (ROS) are destroyed, preventing cellular damage that accumulates over time and causes aging.  Birds therefore age slowly and maintain their youthful function throughout the vast majority of their years.

Other animals, including humans, might be able to benefit from research that targets these proteins.  A growing body of research aimed at treating obesity has a similar goal, and gene therapies that are aimed at stimulating “brown fat” promise to kill two birds with one stone.   Brown fat, a vascular active form of adipose tissue, burns fats rapidly in the presence of oxygen and uncoupling proteins to generate heat.  This is the fat that allows long-lived walruses and cetaceans to keep warm even with wet skin in freezing climates by using fat as nothing more than fuel for the furnace.  Through gene regulation to stimulate brown fat we might be able to reduce obesity and inflammation caused by ROS.

Current research is promising, with the side benefits that gene therapies that increase the activity of the brown fat also cause marked increase in muscle mass and strength, at least in lab mice[2][3].  Scientists at Virginia Tech have recently identified a small mitochondrial uncoupler, named BAM15, that decreases the body fat mass of mice without affecting food intake and muscle mass or increasing body temperature. The research of Santos and colleagues, published in Nature Communications on May 14, 2020, are especially promising for the treatment of obesity and diseases characterized by inflammation.

Although research on mitochondrial decoupling proteins is ongoing, recent progress is promising, and the implications for medicine are sky-high.

[1] Healy, et. al.  2014  Ecology and mode-of-life explain lifespan variation in birds and mammals.  Proc. Royal Soc. B.  DOI: https://doi.org/10.1098/rspb.2014.0298 or visit https://royalsocietypublishing.org/doi/10.1098/rspb.2014.0298.

[2] Weintraub, Arlene.  2020 Gene therapy cuts fat and builds muscle in sedentary mice on unhealthy diets.  Fierce Biotech. May 11. https://www.fiercebiotech.com/research/gene-therapy-cuts-fat-and-builds-muscle-sedentary-mice-unhealthy-diets.

[3] Tang et. al. 2020  Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet–induced obesity.   Science Adv. 08 May 2020:Vol. 6, no. 19. DOI: 10.1126/sciadv.aaz7492 or https://advances.sciencemag.org/content/6/19/eaaz7492.

[4]  https://www.sciencedaily.com/releases/2020/06/200608132539.htm?utm_content=131524119&utm_medium=social&utm_source=twitter&hss_channel=tw-463200485

Will Big Pharma Sabotage its’ Own Re-Shoring?

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The need to reshore American products has been recognized on a federal level for many decades, with legislation such as the original Buy American Act, dated to 1933.

The urgency has grown in recent years, with the burgeoning dependence of the United States on foreign medicines and medical equipment now constituting a huge strategic burden.  The issue has recently come to forefront because of  renewed distrust in supply chain stability thanks to Covid-19, however, and current legislation is upping the ante by including Big Pharma among the list of key players that need to be reformed.

The imperative to return American products home is primarily being addressed through legislation offering incentives aimed at making American businesses more competitive, imposing tariffs on foreign goods and offering tax benefits for American manufacturers.  Although 28% of registered worldwide pharmaceutical API manufacturing sites are located within the US, according to government statistics when we consider the sourcing of raw materials, various estimates suggest that the true foreign dependence is even higher.  Indeed, it is surprisingly difficult for consumers to determine the origin of their drugs and medicines, and many pharmaceutical companies are reticent about their suppliers given the proprietary nature of the information.

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President Trump’s proposed “Buy America” Executive Order, spearheaded by White House trade adviser Peter Navarro, was sidelined by the National Security Council before it could be signed last Friday.  Although the exact details of the order are under negotiation, it is clear that the future of the pharmaceutical industry is at a major crossroads: what happens when the order is signed will shape the manufacturing of pharmaceuticals worldwide.

While this situation underscores the necessity for re-shoring American manufacturing of pharmaceuticals, the biggest opposition to the movement is coming from pharmaceutical lobbyists on Capitol Hill.  Perhaps this is unsurprising, given the enormous disruptions that changing the system would cause, and the fact that many of the losers would be large, powerful corporations with pronounced sourcing from overseas.  Nevertheless, the Pharmaceutical Research and Manufacturers of America (PhRMA), which is the largest pharma lobbying group present, has proffered an argument that re-shoring proposals will “… not only overestimate the potential feasibility and underestimate the time and effort it would take to make such changes, but also misunderstand that a diverse pharmaceutical supply chain is precisely what enables the industry to respond quickly and make adjustments in its supply chain sourcing during natural emergencies and global public health crises.”

Some of this rhetoric is true:  the process will definitely be expensive and difficult.  Some of this is false: parallel supply chains increases the robustness of the worldwide supply.  In fact, redundancy is a key element to airplane safety, and by analogy, it’s plain to see that parallel sources are far more secure than relying on a potentially distant source in an emergency.  This resistance is troubling, since the truth is staring us in the face:  global supply chains are not always reliable.  Imports from China for critical medicines and pharmaceuticals are being cut off entirely due to Covid-19.  This dependence has placed lives at risk since 90 percent of the generic medications that Americans use daily are imported.

The reluctance of  Big Pharma to reduce an unhealthy and greedy dependence on cheap labor and materials will have serious consequences for American healthcare as well as national security.  China’s dominance of the pharma supply chain is highly dangerous to the United States.  Pharmaceutical production must be reshored and even expanded in order to develop secure and safe supply chains for medications, vaccines and medical devices. This crossroads brings us to a critical question: will the United States commit its financial might to developing American pharmaceutical manufacturing capabilities, or will pharma itself stand in the way?